Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial.

Abstract

BACKGROUND:

The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis.

METHODS:

We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498.

FINDINGS:

Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group.

INTERPRETATION:

Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification.

FUNDING:

National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

• Authors: Brent A Neuschwander-Tetri, Rohit Loomba, Arun J Sanyal, Joel E Lavine, Mark L Van Natta, Manal F Abdelmalek, Naga Chalasani, Srinivasan Dasarathy, Anna Mae Diehl, Bilal Hameed, Kris V Kowdley, Arthur McCullough, Norah Terrault, Jeanne M Clark, James Tonascia, Elizabeth M Brunt, David E Kleiner, Edward Doo, NASH Clinical Research Network
• Journal: Lancet (London, England) (Lancet) Vol. 385 Issue 9972 Pg. 956-65 (Mar 14 2015) ISSN: 1474-547X [Electronic] England
• PMID: 25468160 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Cholesterol, HDL
• Cholesterol, LDL
• Receptors, Cytoplasmic and Nuclear
• obeticholic acid
• farnesoid X-activated receptor
• Chenodeoxycholic Acid

Topics

• Administration, Oral
• Chenodeoxycholic Acid (administration & dosage, adverse effects, analogs & derivatives)
• Cholesterol, HDL (metabolism)
• Cholesterol, LDL (metabolism)
• Double-Blind Method
• Female
• Humans
• Liver (enzymology)
• Liver Cirrhosis (drug therapy)
• Male
• Middle Aged
• Non-alcoholic Fatty Liver Disease (drug therapy, enzymology)
• Receptors, Cytoplasmic and Nuclear (drug effects)
• Treatment Outcome
• Weight Loss (drug effects)